A Revolution in Cancer Care: Cancer Immunotherapeutics in the Pipeline

In the past several years, great progress has been made in understanding the components of the immune system that are necessary for tumor control and in developing immunotherapies that help to more effectively fight cancer. Even when used as single agents in patients with advanced and rapidly progressive disease, some immunotherapies have demonstrated significant efficacy, suggesting promising potential for even greater efficacy if used in combination with other drugs and in earlier stage disease to effect long-term tumor control (Finn, 2012).

Many biopharmaceutical manufacturers recognize this significant market potential in immunotherapy and are aggressively expanding their pipelines (e.g., the recent acquisition of Costim Pharmaceuticals, a biotech company developing PD-1/PD-L1 inhibitors by Novartis).

Promising approaches in the development of immunotherapies and their associated mechanisms of action in the pipeline include:

Immune Checkpoint Inhibition, and

Adoptive Therapy

Immune Checkpoint Inhibitors

Immune checkpoint pathways downregulate immune system activity to minimize collateral tissue damage caused by the immune response. Some tumors have been shown to hijack these immune checkpoint pathways in order to develop immune resistance and evade the body’s immune cells. By inhibiting molecules involved in immune checkpoints, the immune system can receive a “boost,” allowing the immune cells to function more effectively to fight the tumor (Pardoll, 2012).

In 2011, Bristol-Myers Squibb’s (BMS) immune checkpoint inhibitor, ipilimumab (Yervoy), gained FDA approval for unresectable or metastatic melanoma. Ipilimumab’s approval was a milestone both in the treatment of melanoma and in the development history of immunotherapies.

Results of ongoing data involving 1,800 patients with melanoma treated with ipilimumab demonstrate that 22% of patients were still alive after 3 years. Following ipilimumab’s approval and subsequent success, a race began between manufacturers to improve upon this novel immunotherapeutic method.

Several therapies have already entered their final stages of development, which include BMS’s nivolumab, Merck’s MK-3475, both target PD-1 on T cells, and Roche’s MPDL3280A, which blocks PD-L1 on tumor cells.

BMS’s Nivolumab

Nivolumab is a monoclonal IgG4 antibody that blocks PD-1 on CD8+ T cells, tumor infiltrating lymphocytes (TILs), preventing PD-1 from interacting with PD-L1 (Creelan, 2014). In long-term follow up of a Phase 1 study of nivolumab in 107 patients with heavily pre-treated advanced metastatic melanoma, nivolumab demonstrated durable responses out to 2 years with a median estimated overall survival of 16.8 months and one- and two-year survival rates of 62% and 43%, respectively (Topalian, 2014).

In addition, 12 of 17 patients who discontinued the drug for reasons other than disease progression continued to respond to the treatment for at least 16 weeks and up to 56 weeks after discontinuation. The response rates in melanoma and toxicity profile of nivolumab compare favorably with those of ipilimumab and BRAF inhibitors (Topalian, 2014, Medscape 2014).

“In this study, even after the treatment was stopped, these responses continued,” said Suzanne Topalian, professor of surgery and oncology at the Johns Hopkins University School of Medicine, and director of the Melanoma Program at the Kimmel Cancer Center, in a statement to Medscape Medical News. “And without any further therapy, most of the patients remained in response for a very long time. In fact, one patient's tumor continued to shrink after the drug was stopped,” (Medscape, 2014).

Topalian explains that because the drug amplifies the immune response rather than targeting a specific mutation, it has the potential to treat patients whose cancers harbor many different types of mutations. In addition, although the best schedule for administration of PD-1 and PD-L1 blockers has not yet been determined, these therapies have the potential to emerge as a type of booster vaccine regimen, where patients may visit the clinic regularly to get their immune system boosted (Medscape, 2014).

BMS is currently conducting a series of Phase 3 trials (the Checkmate series) to further assess the efficacy of nivolumab, including two trials for NSCLC comparing the drug with docetaxel (NCT01642004, NCT01673867), one trial for advanced or metastatic clear-cell renal cell carcinoma compares it with everolimus (NCT01668784), and a study testing nivolumab in combination with ipilimumab for advanced melanoma (NCT01844505).

Merck’s MK-3475

Merck’s MK-3475 is a highly selective anti-PD1 inhibitor. It is designed to block the interaction between PD1 and its ligands, PD-L1 and PD-L2, with the goal of restoring the immune system’s ability to recognize and target tumor cells. The drug received Breakthrough Therapy designation status from the FDA based on interim results from a Phase 1b study in patients with advanced melanoma (Merck, 2013).

In the study, 43 patients (out of 85 evaluable) showed an objective anti-tumor response, 8 of which showed complete response. In addition, 11 of 27 patients who had been treated previously with ipilimumab demonstrated an objective anti-tumor response (Merck, 2012). Last October, Merck released interim data from a Phase 1B trial evaluating MK-3475 in patients with previously treated NSCLC. In the 38 patient cohort the objective response rate was 24% based on immune-related response criteria (irRC) and a 21% rate by RECIST criteria (n=33).

The median overall survival at the time of analysis was 51 weeks with 7 out of 9 responders by irRC continuing on treatment, and the median duration of response had not been reached. High levels of PD-L1 expression were correlated with higher response rates than low levels (67% [6/9]) by irRC and 57% [4/7] by RECIST vs. 4% by irRC [1/24] and 9% [2/22] by RECIST, respectively]) (Merck, 2013).

Since the drug’s Breakthrough Therapy designation, a total of 16 clinical trials have opened assessing the efficacy of MK-3475 across various tumor types.